Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are potentially curable by[unreadable] hematopoietic cell transplantation (HCT). However, disease progression/relapse in patients with more[unreadable] advanced disease and regimen-related toxicity and transplant-related complications, in particular, graftversus-[unreadable] host disease (GVHD), remain problems that lead to non-relapse mortality (NRM). The use of[unreadable] reduced-intensity/nonmyeloablative conditioning regimens has reduced acute NRM but has not eliminated[unreadable] the problem of GVHD, particularly in its chronic form, and has been associated with disease[unreadable] progression/relapse. The overall objective of this Project is to optimize HCT strategies for patients with MDS[unreadable] transplanted from related or unrelated, HLA-identical or -nonidentical donors. Specifically, in Aim 1, we will[unreadable] carry out a multi-center, randomized prospective study comparing efficacy of myeloablative and[unreadable] nonmyeloablative conditioning, and determine overall survival with either approach. In Aim 2, we will[unreadable] conduct a pilot trial of total body irradiation (TBI) dose escalation in conjunction with fludarabine (Flu) to[unreadable] prevent disease progression and graft failure in patients with high-risk MDS who have not received[unreadable] chemotherapy before HCT. In Aim 3, we will a) determine whether reduction of the CDS cell content from GCSF[unreadable] mobilized peripheral blood mononuclear cells will reduce the incidence of GVHD after transplants from[unreadable] HLA-identical family members without increasing the risk of graft failure; b) further refine the use of in vivo[unreadable] T-cell depletion by Thymoglobulin in conjunction with Flu plus busulfan conditioning in patients transplanted[unreadable] from related or unrelated donors. In Aim 4, we will determine a) whether conditioning with Flu/TBI[unreadable] (+/-Campath(R)) allows for HCT from HLA class I mismatched unrelated donors; b) whether conditioning with[unreadable] Flu/TBI and cyclophosphamide before and after transplantation allows for HCT from haploidentical related[unreadable] donors. In Aim 5, we will continue long-term observation of patients with MDS who have undergone HCT to[unreadable] generate a database of late results. We expect these studies to provide definitive data with myeloablative as[unreadable] compared to nonmyeloablative HCT in comparable patient cohorts, reduce the incidence of GVHD and[unreadable] disease progression, broaden the indications of HCT for patients with MDS, and assess late results with[unreadable] HCT. Knowledge gained from these studies should allow us to offer HCT to more patients with MDS, and to[unreadable] improve the success rate and long-term survival.[unreadable]